The purchase of this research is to determine the mechanisms and factors that establish and maintain tubular diameter, to understand the pathobiology of PKD, and to use this information to find a therapy for polycystic kidney diseases (PKD).
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 (approximately 85 percent) or PKD2 (approximately 15 percent) and is the most common genetic cause of PKD. It is mainly characterized by cystic dilatation of the kidney and biliary tubular epithelium. Our focus is to understand how these genes are involved in the establishment of normal tubular diameter and how their inactivation leads to cyst formation. To this end, we currently use several (conditional) knock-out mice and cell lines to study gene expression patterns, metabolic profiles, protein interactions, intracellular trafficking, and signaling pathways.
While the PKD gene products polycystin 1 (PC1) and polycystin 2 (PC2) are known to be essential for establishing and maintaining normal tubule structure, we do not know what they do. Several lines of evidence suggest that they function as a receptor-channel complex, but what they sense and signal is poorly understood. Though numerous pathways have been reported to be dysregulated in cystic epithelia, it is unclear how these link back to the function of the PC1/PC2 complex, which pathways are dysregulated at the earliest stages of cyst formation, and which are altered as secondary consequence of cystic dilations. We also do not understand why cysts form immediately after gene inactivation in young mice, but take months to arise in older animals. What factors preserve tubular structure during this interval, and what triggers the subsequent failure?
Understanding these processes is important not only from a pathobiological standpoint, but also to design more specific therapies. We also need better tools to assess the progression of disease so we can better evaluate the effectiveness of clinical interventions. Clinical trials are testing promising drugs, and some have reported encouraging results. However, the measure of improvement is often kidney/cyst size, which doesn’t always correlate with improvement in kidney function. A more thorough understanding of PKD biology will likely shed light on this matter, but in the meantime, biomarkers of early progression and additional measures of outcome in clinical trials should be sought and evaluated.